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Original article
The association between apelin-12 levels and paroxysmal
supraventricular tachycardia
Mehtap Gurgera, Ahmet Celikb, Mehmet Balinb, Evrim Gula, Mehmet A. Kobatb,
Kazım B. Bursalia, Mustafa Sahana, Umut Gumusaya, Cagdas Cana,
Ilyas M. Celikera, Suna Aydinc and Suleyman Aydind
Aims Our aim was to investigate the apelin-12 levels in
patients with atrioventricular tachyarrhythmias and
compare with those in patients with lone atrial fibrillation.
90%, respectively (cut-off value was 0.87). The area under
the receiver operator characteristic curve was 0.834 for the
apelin-12 levels (P U 0.0001).
Methods Forty four patients with supraventricular
tachycardia as atrial fibrillation, 44 patients with paroxysmal
supraventricular tachycardia (P-SVT) as atrioventricular
tachyarrhythmias, including atrioventricular nodal reentrant
tachycardia or atrioventricular reentrant tachycardia, and 30
age- and sex-matched healthy individuals were included in
the study.
Conclusion Apelin-12 levels are lower in patients with
atrial fibrillation and P-SVT than control groups. Lower
apelin levels in patients with atrial fibrillation and P-SVT
would be expected to result in a decrease in the conduction
velocity.
J Cardiovasc Med 2014, 15:642–646
Results The apelin-12 levels were significantly lower in both
atrial fibrillation and P-SVT groups than control group. In
post-hoc analysis, there was no significant difference in
apelin-12 levels between atrial fibrillation and P-SVT groups
(P U 0.9). Patients in atrial fibrillation group and patients in
P-SVT group had significantly lower apelin-12 levels than
control group, separately (P <0.001 and P <0.001,
respectively). The sensitivity and specificity values of the
apelin-12 levels for predicting SVT, including both atrial
fibrillation and atrioventricular reentrant tachycardia or
atrioventricular nodal reentrant tachycardia were 64.77 and
Keywords: apelin 12, atrioventricular nodal reentrant tachycardia,
atrioventricular reentrant tachycardia, paroxysmal supraventricular
tachycardia
Introduction
tachyarrhythmia. Atrial fibrillation is an extremely common arrhythmia arising from chaotic atrial depolarization.
The most common cause of paroxysmal SVT is atrioventricular nodal reentrant tachycardia (AVNRT).
The peptide apelin and the apelin receptors are present
in the heart,1,2 the systemic and pulmonary vasculature,
and there were studies that showed the changes of plasma
apelin levels in myocardial infarction,3 heart failure,4–8
and pulmonary hypertension.4,9 In heart failure patients,
the concentration of apelin was 200-fold higher in atrial
tissue than in left ventricular tissue. Plasma apelin concentrations correlated to atrial apelin levels, and it was
thought that atrial apelin might be an important source of
apelin in plasma.5 Apelin protein levels were upregulated
in left ventricular tissue, but were lower in atrial tissue
from patients with heart failure compared with healthy
controls.5 The other studies researching the plasma levels
of apelin in heart failure patients have reported the
downregulation of the apelin system.4,7,8
a
Department of Emergency, bDepartment of Cardiology, cDepartment of
Cardiovascular Surgery, Elazig Education and Research Hospital and
d
Department of Biochemistry, Firat University Medical Faculty, Elazig, Turkey
Correspondence to Ahmet Celik, MD, Department of Cardiology, Elazig
Education and Research Hospital, Elazig, Turkey
Tel: +90 531 792 79 10; fax: +90 424 212 14 61;
e-mail: [email protected]
Received 21 December 2013 Revised 20 January 2014
Accepted 20 January 2014
Previously, the relation between atrial fibrillation and
apelin levels was shown in a few studies.10–12 All of these
studies showed that lower levels of apelin levels were
associated with atrial fibrillation and were related to
the recurrence of arrhythmia.11
No published data exist to date about the level of apelin12 in patients with paroxysmal SVT. So, we aimed to
investigate the apelin-12 levels in patients with atrioventricular tachyarrhythmias and compare with those in
patients with lone atrial fibrillation.
Participants and methods
Paroxysmal supraventricular tachycardia (SVT) is episodic, with an abrupt onset and termination. Manifestations
of SVT are quite variable; patients may be asymptomatic
or they have minor palpitations or more severe symptoms.
SVTs may be classified as an atrial or atrioventricular
1558-2027 ß 2014 Italian Federation of Cardiology
Patient population
From March 2011 to March 2012, 88 consecutive patients
with SVT who were admitted to our emergency room
with palpitations were included in the study. These
participants were matched on the basis of age, sex, and
DOI:10.2459/JCM.0000000000000010
Copyright © Italian Federation of Cardiology. Unauthorized reproduction of this article is prohibited.
Apelin-12 levels in supraventricular tachycardia Gurger et al. 643
ethnicity with 30 controls recruited from a healthy population. Forty four patients with SVT had atrial fibrillation
and the other 44 of them had atrioventricular tachyarrhythmias, including AVNRT or atrioventricular reentrant tachycardia (AVRT). All participants provided
written informed consent. The protocol was approved
by the local ethics committee. Individuals were considered eligible for enrollment if they had persistent
atrial fibrillation and had a structurally normal heart on
echocardiography. Other individuals were considered
eligible for enrollment if they had AVNRT or AVRT
on admission to emergency and had a structurally normal
heart on echocardiography.
Exclusion criteria were as follows: history of coronary
artery disease and heart failure, suspected myocarditis or
pericarditis, diabetes mellitus, unstable angina pectoris,
ST and non-ST-segment elevation myocardial infarction,
impaired renal function (creatinine 1.4 mg/dl), unstable
endocrine or metabolic diseases, patients with concomitant inflammatory diseases such as infections and autoimmune disorders, acute/chronic hepatic or hepatobiliary
disease, pulmonary hypertension, and malignancy.
All participants underwent standard 12-lead electrocardiogram at enrollment and were evaluated by a cardiology
specialist in the emergency room. A standardized echocardiogram was also obtained from each individual. The
echocardiograms were carried out by a cardiology specialist in the echocardiography laboratory in our cardiology
department. The echocardiography was performed by
Vivid 3 instruments (GE Medical Systems, Milwaukee,
Wisconsin, USA), with a 2.5-MHz transducer and harmonic imaging. Left ventricular ejection fraction was
assessed using the modified biplane Simpson’s method.
Blood sampling and laboratory methods
Blood samples of all individuals were taken from an
antecubital vein following an electrocardiogram. Plasma
was extracted, aliquoted, and stored at 708C until
analysis. Plasma apelin-12 levels were determined using
a commercially available enzyme immunoassay without
Table 1
extraction (Phoenix Pharmaceuticals, Belmont, California, USA) according to the manufacturer’s instructions.
Statistical analysis
Categorical variables were presented as counts and percentages and were compared with the x2 test. Continuous
variables were expressed as means and SD. Student’s
t-test or Mann–Whitney U-test (as appropriate) has been
used for continuous variables between two groups. Comparisons among three groups were carried out using oneway analysis of variance and Tukey’s post-hoc test.
Correlation analyses were performed using the Pearson
or Spearman’s coefficient of correlation. Sensitivity and
specificity values of apelin-12 levels for predicting SVT
were estimated using receiver operator characteristic
(ROC) curve analysis. The cut-off level of apelin-12
levels was determined using MedCalc 9.2.0.1 (MedCalc
Software, Mariakerke, Belgium). A trial version of (demo)
SPSS 15.0 software was used for basic statistical analysis
(Version 15; SPSS Inc., Chicago, Illinois, USA). A value of
P <0.05 was accepted as statistically significant.
Results
The baseline characteristic properties of study patients
are summarized in Table 1. There were no significant
differences among the three groups with respect to sex
distribution, age, frequencies of major coronary risk factors (i.e., diabetes mellitus, hypertension, dyslipidemia,
smoking, family history of coronary artery disease), serum
creatinine, calcium, potassium, total cholesterol, lowdensity lipoprotein cholesterol, high-density lipoprotein
cholesterol, triglycerides, left ventricular ejection fraction, left atrial diameter, SBP, and DBP (P >0.05 for all).
The heart rate of control group was significantly low as
compared with atrial fibrillation and SVT groups.
The apelin-12 levels were significantly lower both in
atrial fibrillation and SVT groups than the control group
(Fig. 1). In post-hoc analysis, there was no significant
difference in apelin-12 levels between atrial fibrillation
and SVT groups (P ¼ 0.9). Patients in the atrial fibrillation
group and patients in the SVT group had significantly
The characteristics of study participants
Age (years)
Women (%)
History of (%)
Diabetes mellitus
Hypertension
Smoke
Creatinine (mg/dl)
Hemoglobin (mg/dl)
White blood cell count
Troponin I
SBP (mmHg)
DBP (mmHg)
Heart rate (beat/min)
Lone AF group (n ¼ 44)
PSVT group (n ¼ 44)
Control group (n ¼ 30)
P
45 7
60.5
42 9
55.6
40 8
56.7
0.3
0.8
11.6
18.6
20.9
0.90 0.20
13.5 1.8
10 3
0.04 0.04
131 18
76 11
142 21
13.3
24.4
17.8
0.86 0.19
13.6 1.7
10.3 3
0.03 0.04
137 22
78 14
146 27
10
13.3
16.7
0.89 0.20
13.9 1.4
8.9 2.7
0.02 0.02
130 18
77 12
84 14
0.6
0.2
0.9
0.5
0.6
0.1
0.1
0.2
0.8
<0.001
Data expressed as mean SD or percentage. AF, atrial fibrillation; PSVT, paroxysmal supraventricular tachycardia. P <0.05 was accepted as statistically significant.
Copyright © Italian Federation of Cardiology. Unauthorized reproduction of this article is prohibited.
644 Journal of Cardiovascular Medicine 2014, Vol 15 No 8
Fig. 1
Fig. 3
2
100
P < 0.001
80
1
Apelin-12 levels
(ng/mL)
0.5
Sensitivity
1.5
60
criterion <= 0.87
AUC = 0.834
95% CI = 0.754–0.896
SE = 0.048
P = 0.0001
40
20
0
0
AF
group
0
P-SVT Control
group
group
The difference in apelin levels among three groups [0.87 0.43 in the
atrial fibrillation group, 0.81 0.28 in the paroxysmal supraventricular
tachycardia (P-SVT) group, and 1.94 1.55 in the control group,
P <0.001].
lower apelin-12 levels than the control group, separately
(P <0.001 and P <0.001, respectively).
Figure 2 shows the Pearson correlation analysis of apelin12 levels and heart rate. Apelin-12 levels were highly
negatively correlated with the heart rate of the study
participants (r ¼ 0.608 and P <0.001).
ROC analysis was used to identify the ability of apelin-12
levels to predict the SVT and is shown in Fig. 3. We
accepted both patients with atrial fibrillation and P-SVT
groups as SVT Group for this analysis. The area under the
ROC curve was 0.834 for the apelin-12 levels
(P ¼ 0.0001). The sensitivity and specificity values of
the apelin-12 levels were 64.77 and 90%, respectively
(cut-off value was 0.87).
Discussion
We have demonstrated that the apelin-12 levels were
significantly lower both in the atrial fibrillation and
paroxysmal SVT groups than the control group.
20
80
40
60
100-Specificity
100
Receiver operator characteristic curve of apelin-12 levels in study
patients for predicting supraventricular tachycardia. AUC, area under
curve; CI, confidence interval.
Apelin is a peptide that is the ligand for the APJ (angiotensin receptor like-1) receptor.8,13 Apelin and APJ are
widely distributed in the vasculature of organs.8 Apelin
mRNA expression was found in the gastrointestinal tract,
adipose tissue, brain (corpus callosum, amygdala, substantia nigra, and pituitary), spinal cord, lung, kidney,
liver, skeletal muscle, and cardiovascular system.14,15 In
the cardiovascular system, apelin has been detected in
endothelial cells of large conduit arteries, coronary
vessels, and endocardium of the right atrium.14
Apelin–APJ system plays a role in regulation of fluid16
and glucose homeostasis, feeding behavior, vessel formation, cell proliferation and immunity.17
In the cardiovascular system, apelin is a potent vasodilator14,18,19 with a strong positive inotropic effect.8,13,17
The vasodilatation effect of apelin is connected with
nitric oxide and it may also be because of the fact that
APJ receptors counteract the pressure effect of angiotensin II.14 Apelin is a coronary vasodilator and reduces
peripheral vascular resistance. Intravenous apelin administration in rodents reduces mean arterial pressure and
systemic venous tone.18
Apelin-12 levels (ng/mL)
Fig. 2
Apelin has been shown to exert potent positive inotropic
effects on both normal and failing myocardium20 by
increasing intracellular calcium rather than enhancing
the calcium sensitivity of the myofilaments.13,21 The inotropic response to apelin may involve activation of phospholipase C, protein kinase C, and sarcolemmal sodium
hydrogen exchange, and sodium calcium exchange.21 In
humans, apelin was reduced in patients with left ventricular dysfunction secondary to ischemic heart disease,
congestive heart failure, and dyslipidemia.13,21,22
r = –0.608, p < 0.001
6.00
4.00
2.00
r = 0.245
0.00
60.00
80.00 100.00 120.00 140.00 160.00 180.00 200.00
Heart rate (beat/min)
The correlation analysis of apelin-12 levels and heart rate in all study
patients.
Paroxysmal SVT is a common cardiac arrhythmia presenting to emergency departments.23 It can be benign
and self-limiting. Patients may present with distressing
symptoms of palpitations, dizziness, fatigue, and weakness; however, patients may also experience serious
complaints or symptoms, including angina, dyspnea,
hypotension, or congestive heart failure.24,25
Copyright © Italian Federation of Cardiology. Unauthorized reproduction of this article is prohibited.
Apelin-12 levels in supraventricular tachycardia Gurger et al. 645
There are three accepted mechanisms for tachyarrhythmias: increased automaticity in a normal or ectopic site,
reentry in a normal or accessory pathway, and after
depolarizations causing triggered rhythms. About 60%
of patients with SVT have reentry within the atrioventricular node (AVNRT), and 20% have reentry involving
a bypass tract (AVRT). The remaining have reentry in
other sites.25 Reentry can occur in atrioventricular node,
in atrium, and between atrioventricular node and accessory pathways. Paroxysmal SVT can occur by reentry in
atrioventricular node or between atrioventricular node
and the accessory pathway.26 The underlying mechanism
of atrial fibrillation is still debated. Cellular proarrhythmic
mechanisms (automaticity and triggered activity) and
reentrant mechanisms might underlie atrial fibrillation.
Shortening of atrial refractoriness and reentrant wavelength or local conduction heterogeneities and changes in
ion channel function may occur in patients with atrial
fibrillation.27
Low levels of the regulatory peptide apelin have been
reported in patients with lone atrial fibrillation.10–12
Kallergis et al.10 demonstrated that apelin levels are lower
in patients with persistent, long-lasting, lone atrial fibrillation and they found that successful cardioversion of
atrial fibrillation led to a significant increase in plasma
apelin levels. Similarly, Falcone et al.11 demonstrated that
significantly lower apelin plasma levels were found in
patients with atrial fibrillation recurrence with respect to
population with persistence of sinus rhythm during a
6-month follow-up. These studies show that apelin
may play an important role in intercellular communication. In the present study, we showed the relationship
between apelin and patients with atrial fibrillation and
paroxysmal SVT like other studies. We showed high
negative correlation between heart rate and serum apelin
levels in our study. This result supports the finding of
study by Kallergis et al. because they found an increase in
apelin levels when they supplied sinus rhythm in atrial
fibrillation patients. After conversion of atrial fibrillation
to sinus rhythm, the heart rate will decrease and become
regular. So our study first shows the relation between
heart rate and serum apelin levels.
exchanger current, but decreased late sodium current and
calcium currents and did not change transient
outward current or inward rectifier potassium currents
in rabbit left atrial myocytes, so apelin affected the
electrophysiology of left atrial myocytes and hence led
to a shortening of axion potential duration via regulation
of various ionic currents.
L-type
Lower apelin levels in patients with atrial fibrillation and
PSVT would be expected to result in a decrease of the
conduction velocity. Slowing conduction leads to a
shorter wavelength, facilitates conduction block, and
permits a larger number of re-entering wavelets to coexist
in the atria and atrioventricular node.
The arrhythmogenic role of apelin needs to be investigated further. In conclusion, our results demonstrate that
apelin levels are lower in patients with atrial fibrillation
and PSVT than control groups and highly correlated with
heart rate.
Acknowledgements
No funding supported this study.
There are no conflicts of interest.
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